Severe cutaneous adverse reactions associated with systemic ivermectin: A pharmacovigilance analysis

Abstract Despite poor evidence, the antiparasitic ivermectin has been advocated as a potential COVID‐19 therapy. This has led to a rise in calls to poison‐control centers by people self‐medicating with ivermectin, which is sold over the counter for veterinary uses. We aimed to investigate the association between severe cutaneous adverse reactions (SCARs) and ivermectin. Postmarketing data from the FDA Adverse Event Reporting System (FAERS), gathered between 2014 and 2021, was employed to detect disproportional signals of SCARs following systemic ivermectin therapy. The reporting odds ratio (ROR) was used to quantify the strength of association, while adjusting for age, sex, and region. The search yielded 517 reports of systemic ivermectin (median age 54 years, 46.8% female), of which 25 (4.8%), 81 (15.7%), and 411 (79.5%) were classified as SCARs, nonsevere cutaneous adverse events (AEs), or noncutaneous AEs, respectively. The regional distribution differed between SCAR reports (32.0% from Africa and 12.0% from North America) compared with other AEs, which originated from North America in over half of cases. The most common SCARs were toxic epidermal necrolysis (seven cases), Stevens–Johnson syndrome (seven cases), and drug reaction with eosinophilia and systemic symptoms (four cases). Five SCAR cases (20.0%) resulted in death and 12 (48.0%) lead to hospitalization. There was a strong safety signal for any SCAR (adjusted ROR 3.34, 95% confidence interval [CI] 2.17–5.12) and toxidermias (adjusted ROR 7.08, 95% CI 4.23–11.84). This study suggests that ivermectin is associated with SCARs on rare occasions. Dermatologists should be aware of this given the increase in ivermectin misuse.

in the recommended dosages, some rare events may go undetected in clinical trials or retrospective cohorts. Therefore, postmarketing surveillance data, aggregated from spontaneous reports, is a useful tool for investigating rare AEs and severe cutaneous adverse reactions (SCARs) in particular.

| ME THODS
This was a retrospective analysis of postmarketing safety data from the FDA Adverse Event Reporting System (FAERS), collected between July 2014 and June 2021. FAERS utilizes the Medical Dictionary for Regulatory Activities (MedDRA), a hierarchical and rigorously maintained standardized terminology of medical concepts. Duplicate reports were recognized as those with overlaps in at least three out of four key fields: date, age, gender, and country. 4 We selected reports in which orally administered ivermectin was the primary suspect and adopted a conservative approach by assuming topical ivermectin was used in cases where the indication was lice infestation, acarodermatitis, or rosacea and the route of administration was unknown. Acarodermatitis is a MedDRA term that may be used to indicate any of the following conditions: acarodermatitis, Norwegian scabies, Sarcoptes scabiei infestation, scabies, and scabies infestation. 5 Severe cutaneous adverse reactions (SCARs) were defined according to the Standardized MedDRA Query (SMQ). If a case reported both Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), it was considered only as TEN, since these conditions lie on a disease spectrum.
We employed a disproportionality analysis to estimate safety signals from spontaneous AE reports, 4 using the validated reporting odds ratio (ROR), which is the odds of reporting a specific AE versus all other AEs under a certain product, compared to all other products available in FAERS. The ROR is analogous to the odds ratio in a case-control study where the exposure is ivermectin and the outcome is reporting of SCAR. Multivariate logistic regression was performed using age, sex, region, and ivermectin use as covariates for calculating the adjusted odds of SCAR. The Kruskal-Wallis or χ 2 tests were used to compare continuous or categorical data across groups, respectively, setting a significance level of 0.05. All statistical analyses were performed in R, version 3.5.0. Because data are publicly available, ethics approval was not required.  (Table 1). Within SCAR cases, the median age was 43 years (IQR 29-69.25 years) and 48.0% were female. The median dosage was 9 mg (IQR 3.75-12 mg) and the median time to onset was 3 days (IQR 1.5-7.25 days), although this information was missing for more than half of cases. Age and sex did not differ between the three groups (P = 0.355 for age comparison, P = 0.178 for sex comparison), as well as dose and time to onset (P = 0.075 and P = 0.270, respectively). SCAR cases originated from Africa (8/25 cases, 32.0%), Europe (7/25 cases, 28.0%), Asia (6/25 cases, 24.0%), and North America (3/25 cases, 12.0%). This was in contrast to the other cases, which originated from North America in over 50% of cases, but from Africa in less than 10% of cases (χ 2 = 25.85, P < 0.001).

| RE SULTS
The most common indications were acarodermatitis due to mite infestation and helminthic infections, including filariasis, onchocerciasis, and strongyloidiasis. In a few cases concomitant drugs previously associated with SCARs were reported as secondary suspects (two cases of amoxicillin and one case of valproic acid). The most common SCARs were TEN, SJS, and drug reaction with eosinophilia and systemic symptoms (DRESS), occurring in seven (28.0%), seven (8.0%), and four (16.0%) cases, respectively ( Figure 1). Among SCAR cases, five (20.0%) resulted in death and 12 (48.0%) in hospitalization. The most common nonsevere cutaneous AEs were pruritus (31 cases, 38.3%), rash (16 cases, 19.8%), and angioedema (11 cases, 13.6%). Death was reported in four cases (4.9%) of nonsevere cutaneous AEs, but was due to other co-occurring AEs such as sepsis or other organ failure.

| DISCUSS ION
Ivermectin has been used for more than three decades for treating filariasis, onchocerciasis, and strongyloidiasis in humans, as well as other dermatologic conditions such as scabies, lice infestation, or demodicosis. While generally safe at recommended dosages, 6 ivermectin may lead to pruritus, lymphadenitis, arthralgia, and fever, sometimes as part of the Mazzotti reaction. Although the most serious ivermectin safety concern is rare neurotoxicity, 5 several cases of SCARs following systemic ivermectin have been reported in recent years. 7-10 Our search yielded 25 cases of ivermectinrelated SCARs, mostly SJS, TEN, and DRESS, with a 20% mortality.
Disproportionality analysis revealed a significant association between systemic ivermectin and reporting of any SCARs, confirming a recent study of VigiBase, another pharmacovigilance database. 11 Interestingly, SCARs were reported more in African countries

ACK N OWLED G M ENTS
All authors contributed to the study conception and design. Material preparation, data collection, and analysis were performed by D.B. The entire FAERS database, excluding cases with missing covariates, was used to calculate a reporting odds ratio (ROR). The ROR is therefore analogous to an odds ratio in a case-control design, where the exposure is the drug (e.g. ivermectin) and the outcome is reporting of an AE of interest (e.g. SCAR or toxidermias). b Two cases originating from Antarctica were excluded, these did not report any SCARs.
The first draft of the manuscript was written by D.B. and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

CO N FLI C T O F I NTE R E S T
The authors report no conflict of interest.

E TH I C A L A PPROVA L
This study is based on anonymous data that can be downloaded from a publicly available source. Therefore, no ethical approval is required.